Humans continue to be exposed to organic (CH3Hg+) and inorganic (Hg2+) forms of mercury. These environmental toxicants affect numerous organ systems, but a major target for their accumulation and toxicity is the kidney, specifically the proximal tubule. Numerous studies have shown that CH3Hg+ and Hg2+ can be removed from proximal tubules by treatment with the metal chelators, 2,3-dimercapto-1-propanesulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA). This removal appears to involve a conjugation step wherein intracellular mercuric ions form strong bonds with one of these chelators, and a subsequent export step where these mercury-chelator complexes are secreted into the tubular lumen. The actual mechanisms involved in this secretion, however, remain undefined. Yet based on the characteristics of the multidrug resistance proteins (MRP), it is likely that one or more of these proteins are involved in the DMPS- and DMSA- mediated export of mercuric ions. Therefore, the purpose of the current proposal is to test the hypothesis that MRP2, and/or MPR4, play a role in the DMPS- and DMSA-mediated elimination of CH3Hg+ and Hg2+ from the kidney. To test this hypothesis, we will use TR- rats, which do not express the Mrp2 protein, and Madin-Darby canine kidney (MDCK) cells stably transfected with OAT1 and MRP2 or MRP4. We will first examine the effect of DMPS and DMSA on the handling and disposition of CH3Hg+ and Hg2+ in control and TR- rats. As an alternative model, the transfected MDCK cells will be used to study the roles of MRP2 and MRP4 in the export of various species of mercury. The use of these cells allows for the separation of MRP2 and MRP4 activities and enables a more accurate characterization of the role of each protein in the transport of mercuric species. Collectively, these studies will determine whether MRP2 and/or MRP4 play(s) a role in the DMPS- and DMSA- mediated secretion of CH3Hg+ and Hg2+ from proximal tubular cells. The data obtained from these experiments will serve as the basis for a more expanded set of studies. The current and future studies will be important to human health in that they will serve as the basis for the development of additional therapeutic regimes for mercury poisoning. Mercury is a prevalent environmental toxicant to which humans are exposed frequently. The data obtained from the proposed studies will provide important information related to the way in which mercury is eliminated from the body. These data will serve as the basis for the development of additional treatments for mercury poisoning. ? ? ? ?
Showing the most recent 10 out of 12 publications
